ES2486296T3 - Contrast agents - Google Patents
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- ES2486296T3 ES2486296T3 ES08793873.4T ES08793873T ES2486296T3 ES 2486296 T3 ES2486296 T3 ES 2486296T3 ES 08793873 T ES08793873 T ES 08793873T ES 2486296 T3 ES2486296 T3 ES 2486296T3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0452—Solutions, e.g. for injection
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Apparatus For Radiation Diagnosis (AREA)
Abstract
Un compuesto de fórmula (I) R-N(CHO)-X-N(R3)-R (I) o una sal o isómero óptico activo del mismo, en donde X representa un componente alquileno lineal o ramificado de C3 a C8, opcionalmente con uno o dos componentes CH2 sustituidos por átomos de oxígeno, átomos de azufre o grupos NR1 y en donde el componente alquileno está opcionalmente sustituido con hasta seis grupos -OR1; R1 representa un hidrógeno o un grupo alquilo lineal o ramificado de C1 a C4; R3 representa un átomo de hidrógeno, un componente formilo o un componente acetilo; y cada R es independientemente igual o diferente y representa un grupo fenilo triyodado sustituido además con dos grupos R2, en donde cada R2 es igual o diferente y representa un átomo de hidrógeno o un componente hidrófilo no iónico, con tal de que al menos un grupo R2 del compuesto de fórmula (I) sea un componente hidrófilo.A compound of formula (I) RN (CHO) -XN (R3) -R (I) or an active optical salt or isomer thereof, wherein X represents a linear or branched alkylene component of C3 to C8, optionally with one or two CH2 components substituted by oxygen atoms, sulfur atoms or NR1 groups and wherein the alkylene component is optionally substituted with up to six -OR1 groups; R1 represents a hydrogen or a linear or branched C1 to C4 alkyl group; R3 represents a hydrogen atom, a formyl component or an acetyl component; and each R is independently the same or different and represents a triiodinated phenyl group further substituted with two R2 groups, wherein each R2 is the same or different and represents a hydrogen atom or a non-ionic hydrophilic component, provided that at least one group R2 of the compound of formula (I) is a hydrophilic component.
Description
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DESCRIPCIÓN DESCRIPTION
Agentes de contraste Contrast agents
Campo técnico de la invención Technical Field of the Invention
La presente invención se refiere a una clase de compuestos y a composiciones diagnósticas que contienen dichos compuestos, donde los compuestos son compuestos que contienen yodo. Más específicamente, los compuestos que contienen yodo son compuestos químicos que contienen dos grupos fenilo yodados unidos. The present invention relates to a class of compounds and diagnostic compositions containing said compounds, wherein the compounds are iodine-containing compounds. More specifically, iodine-containing compounds are chemical compounds that contain two joined iodinated phenyl groups.
La invención también se refiere al uso de dichas composiciones diagnósticas como agentes de contraste para obtención de imágenes diagnósticas y, en particular, para obtención de imágenes por rayos X, y a medios de contraste que contienen dichos compuestos. The invention also relates to the use of said diagnostic compositions as contrast agents for obtaining diagnostic images and, in particular, for obtaining X-ray images, and for contrast media containing said compounds.
Descripción de la técnica relacionada Description of the related technique
Toda obtención de imágenes diagnósticas se basa en la consecución de diferentes niveles de señal procedentes de diferentes estructuras del organismo. De este modo, por ejemplo, en la obtención de imágenes por rayos X, para que una estructura corporal dada sea visible en la imagen, la atenuación de los rayos X por esa estructura debe diferir de la atenuación de los tejidos circundantes. La diferencia de señal entre la estructura corporal y sus alrededores es denominada frecuentemente "contraste", y se ha dedicado un gran esfuerzo a medios para potenciar el contraste en la obtención de imágenes diagnósticas ya que cuanto mayor sea el contraste entre una estructura corporal y sus alrededores mayor será la calidad de las imágenes y mayor su valor para el médico que realiza el diagnóstico. Además, cuanto mayor sea el contraste más pequeñas serán las estructuras corporales que se podrán visualizar en los procedimientos para obtención de imágenes; es decir, un contraste aumentado puede conducir a una resolución espacial aumentada. All diagnostic imaging is based on the achievement of different signal levels from different body structures. Thus, for example, in obtaining X-ray images, so that a given body structure is visible in the image, the attenuation of the X-rays by that structure must differ from the attenuation of the surrounding tissues. The difference in signal between the body structure and its surroundings is often called "contrast", and great effort has been devoted to means to enhance the contrast in obtaining diagnostic images since the greater the contrast between a body structure and its surroundings the greater the quality of the images and the greater their value for the doctor making the diagnosis. In addition, the greater the contrast, the smaller the body structures that can be visualized in the procedures for obtaining images; that is, an increased contrast can lead to an increased spatial resolution.
La calidad diagnóstica de las imágenes depende en gran medida del nivel de ruido inherente en el procedimiento para obtención de imágenes, y, por lo tanto, se puede ver que la relación entre el nivel de contraste y el nivel de ruido representa un eficaz factor de calidad diagnóstica para las imágenes diagnósticas. The diagnostic quality of the images depends largely on the level of noise inherent in the procedure for obtaining images, and, therefore, it can be seen that the relationship between the level of contrast and the level of noise represents an effective factor of diagnostic quality for diagnostic images.
La consecución de una mejora en dicho factor de calidad diagnóstica ha sido durante mucho tiempo una meta importante y aún sigue siéndolo. En técnicas tales como rayos X, obtención de imágenes por resonancia magnética (MRI; del inglés, magnetic resonance imaging) y ultrasonidos, un planteamiento para mejorar el factor de calidad diagnóstica ha sido introducir materiales que potencian el contraste, formulados como medios de contraste, en la región corporal de la que se quieren obtener imágenes. The achievement of an improvement in this diagnostic quality factor has long been an important goal and still remains. In techniques such as X-rays, magnetic resonance imaging (MRI) and ultrasound, an approach to improve the diagnostic quality factor has been to introduce materials that enhance contrast, formulated as contrast media, in the body region from which you want to obtain images.
Por lo tanto, en el caso de los rayos X, los primeros ejemplos de agentes de contraste eran sales inorgánicas insolubles de bario, que potenciaban la atenuación de los rayos X en las zonas corporales en que se distribuían. Durante los últimos 50 años, el campo de los agentes de contraste para rayos X ha venido dominado por compuestos solubles que contienen yodo. Los medios de contraste comercialmente asequibles que contienen agentes de contraste yodados son normalmente clasificados como monómeros iónicos tales como el diatrizoato (comercializado, por ejemplo, bajo la marca comercial Gastrografen™), dímeros iónicos tales como el ioxaglato (comercializado, por ejemplo, bajo la marca comercial Hexabrix™), monómeros no iónicos tales como el iohexol (comercializado, por ejemplo, bajo la marca comercial Omnipaque™), el iopamidol (comercializado, por ejemplo, bajo la marca comercial Isovue™), el iomeprol (comercializado, por ejemplo, bajo la marca comercial Iomeron™) y el dímero no iónico iodixanol (comercializado bajo la marca comercial Visipaque™). Therefore, in the case of X-rays, the first examples of contrast agents were insoluble inorganic barium salts, which enhanced the attenuation of X-rays in the body areas where they were distributed. For the past 50 years, the field of X-ray contrast agents has been dominated by soluble compounds that contain iodine. Commercially available contrast media containing iodinated contrast agents are normally classified as ionic monomers such as diatrizoate (marketed, for example, under the trademark Gastrografen ™), ionic dimers such as ioxaglate (marketed, for example, under the Hexabrix ™ trademark), non-ionic monomers such as iohexol (marketed, for example, under the trademark Omnipaque ™), iopamidol (marketed, for example, under the trademark Isovue ™), iomeprol (marketed, for example , under the trademark Iomeron ™) and the non-ionic dimer iodixanol (sold under the trademark Visipaque ™).
Los agentes de contraste no iónicos comerciales para rayos X más utilizados, tales como los anteriormente mencionados, son considerados seguros. En más de 20 millones de exámenes con rayos X al año en EE.UU. se usan medios de contraste que contienen agentes de contraste yodados, y el número de reacciones adversas se considera aceptable. Sin embargo, puesto que un examen con rayos X potenciado en cuanto al contraste requerirá hasta aproximadamente 200 ml de medios de contraste administrados en una dosis total, hay un continuo apremio para obtener medios de contraste mejorados. The most commonly used commercial non-ionic X-ray contrast agents, such as those mentioned above, are considered safe. In more than 20 million X-ray exams per year in the US contrast media containing iodinated contrast agents are used, and the number of adverse reactions is considered acceptable. However, since a contrast-enhanced X-ray examination will require up to approximately 200 ml of contrast media administered in a total dose, there is a continuing urge to obtain improved contrast media.
La utilidad de los medios de contraste viene gobernada en gran medida por su toxicidad, por su eficacia diagnóstica, por los efectos adversos que puede ejercer sobre el sujeto al cual se administra el medio de contraste, y por la facilidad de producción, almacenamiento y administración. Puesto que dichos medios se emplean convencionalmente con fines diagnósticos en lugar de para conseguir un efecto terapéutico directo, es generalmente deseable proporcionar medios que ejerzan el menor efecto posible sobre los diversos mecanismos biológicos de las células o del organismo ya que esto conducirá a una menor toxicidad y a un menor efecto clínico adverso. A la toxicidad y a los efectos biológicos adversos de un medio de contraste contribuyen los componentes del medio de formulación, por ejemplo, el disolvente o vehículo así como el propio agente de contraste y sus componentes, tales como los iones de los agentes de contraste iónicos, y también sus metabolitos. The usefulness of contrast media is largely governed by its toxicity, its diagnostic efficacy, the adverse effects it can exert on the subject to whom the contrast medium is administered, and the ease of production, storage and administration. . Since such means are conventionally employed for diagnostic purposes rather than to achieve a direct therapeutic effect, it is generally desirable to provide means that exert the least possible effect on the various biological mechanisms of the cells or organism since this will lead to less toxicity. and to a lower adverse clinical effect. To the toxicity and adverse biological effects of a contrast medium contribute the components of the formulation medium, for example, the solvent or vehicle as well as the contrast agent itself and its components, such as the ions of the ionic contrast agents, and also their metabolites.
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Los principales factores que contribuyen a la toxicidad del medio de contraste se identifican como la quimiotoxicidad del agente de contraste, la osmolalidad del medio de contraste, y la composición iónica del medio de contraste o la carencia de ésta. The main factors that contribute to the toxicity of the contrast medium are identified as the chemotoxicity of the contrast agent, the osmolality of the contrast medium, and the ionic composition of the contrast medium or the lack thereof.
Son características deseables de un agente de contraste yodado una baja toxicidad del propio compuesto (quimiotoxicidad), una baja viscosidad del medio de contraste en que se disuelve el compuesto, una baja osmolalidad del medio de contraste y un elevado contenido de yodo (frecuentemente medido en mg de yodo por ml del medio de contraste formulado para administración). El agente de contraste yodado debe ser además completamente soluble en el medio de formulación, normalmente un medio acuoso, y permanecer en disolución durante el almacenamiento. Desirable characteristics of an iodinated contrast agent are a low toxicity of the compound itself (chemotoxicity), a low viscosity of the contrast medium in which the compound dissolves, a low osmolality of the contrast medium and a high iodine content (often measured in mg of iodine per ml of the contrast medium formulated for administration). The iodinated contrast agent must also be completely soluble in the formulation medium, usually an aqueous medium, and remain in solution during storage.
Las osmolalidades de los productos comerciales, y en particular de los compuestos no iónicos, son aceptables para la mayoría de los medios que contienen monómeros no iónicos y dímeros, aunque aún queda sitio para una mejora. En la angiografía coronaria, por ejemplo, la inyección en el sistema circulatorio de un bolo de medio de contraste ha causado efectos secundarios graves. En este procedimiento, fluye medio de contraste en vez de sangre a través del sistema durante un corto periodo de tiempo, y las diferencias en cuanto a las naturalezas química y fisicoquímica entre el medio de contraste y la sangre que sustituye pueden causar efectos negativos indeseables, tales como arritmias, prolongación del intervalo QT y reducción de la fuerza contractiva cardiaca. Dichos efectos se ven, en particular, con agentes de contraste iónicos, donde los efectos osmotóxicos se asocian con la hipertonicidad del medio de contraste inyectado. Son particularmente deseados los medios de contraste que son isotónicos o ligeramente hipotónicos con respecto a los fluidos corporales. Los medios de contraste con baja osmolaridad presentan baja toxicidad renal, lo que es particularmente deseable. La osmolalidad es una función del número de partículas por unidad de volumen del medio de contraste formulado. The osmolalities of commercial products, and in particular non-ionic compounds, are acceptable for most media containing non-ionic monomers and dimers, although there is still room for improvement. In coronary angiography, for example, injection into the circulatory system of a bolus of contrast medium has caused serious side effects. In this procedure, contrast medium flows instead of blood through the system for a short period of time, and differences in chemical and physicochemical nature between the contrast medium and the blood it replaces can cause undesirable negative effects, such as arrhythmias, prolongation of the QT interval and reduction of cardiac contractive force. Such effects are seen, in particular, with ionic contrast agents, where osmotoxic effects are associated with the hypertonicity of the injected contrast medium. Particularly desirable are contrast media that are isotonic or slightly hypotonic with respect to body fluids. Contrast media with low osmolarity have low renal toxicity, which is particularly desirable. Osmolality is a function of the number of particles per unit volume of the formulated contrast medium.
En pacientes con insuficiencia renal aguda, la nefropatía inducida por el medio de contraste sigue siendo una de las complicaciones más clínicamente importantes del uso de un medio de contraste yodado. P. Aspelin et al., The New England Journal of Medicine, volumen 348: 491-499 (2003), concluyeron que puede que sea menos probable que se desarrolle una nefropatía inducida por el medio de contraste en pacientes de alto riesgo cuando se utiliza iodixanol en lugar de un medio de contraste no iónico de baja osmolaridad. In patients with acute renal failure, contrast-induced nephropathy remains one of the most clinically important complications of using an iodinated contrast medium. P. Aspelin et al., The New England Journal of Medicine, volume 348: 491-499 (2003), concluded that contrast-induced nephropathy may be less likely to develop in high-risk patients when used. iodixanol instead of a non-ionic contrast medium of low osmolarity.
La parte de la población de los pacientes considerados como pacientes de alto riesgo está creciendo. Para satisfacer la necesidad de una mejora continua de los agentes diagnósticos por rayos X in vivo para la población de pacientes completa, hay un apremio continuo para hallar agentes de contraste para rayos X que tengan propiedades mejoradas, también con respecto a la nefrotoxicidad inducida por medios de contraste (CIN; del inglés, contrast induced nephrotoxicity). The part of the population of patients considered as high-risk patients is growing. To meet the need for continuous improvement of diagnostic agents by X-rays in vivo for the entire patient population, there is a continuing urge to find contrast agents for X-rays that have improved properties, also with respect to media-induced nephrotoxicity. of contrast (CIN; from English, contrast induced nephrotoxicity).
Para mantener el volumen de inyección de los medios de contraste lo más pequeño posible, es muy deseable formular los medios de contraste con una elevada concentración de yodo/ml y mantener aún la osmolalidad de los medios en un nivel bajo, preferiblemente por debajo de la isotonicidad o próximo a ella. El desarrollo de agentes de contraste monómeros no iónicos, y en particular de dímeros de bis(triyodofenilo) no iónicos tales como el iodixanol (Patente EP 108638), ha proporcionado medios de contraste con osmotoxicidad reducida que permiten que se alcance una concentración de yodo eficaz para contraste con una disolución hipotónica y ha permitido incluso la corrección del desequilibrio iónico por inclusión de iones plasmáticos mientras se mantiene aún la osmolalidad deseada del medio de contraste Visipaque™ (Documentos WO 90/01194 y WO 91/13636). To keep the injection volume of the contrast media as small as possible, it is highly desirable to formulate the contrast media with a high concentration of iodine / ml and still maintain the osmolality of the media at a low level, preferably below the Isotonicity or close to it. The development of non-ionic monomer contrast agents, and in particular non-ionic bis (triiodophenyl) dimers such as iodixanol (Patent EP 108638), has provided contrast media with reduced osmotoxicity that allow an effective iodine concentration to be achieved. for contrast with a hypotonic solution and has even allowed the correction of ionic imbalance by inclusion of plasma ions while still maintaining the desired osmolality of the Visipaque ™ contrast medium (Documents WO 90/01194 and WO 91/13636).
Los medios de contraste para rayos X con elevada concentración comercial de yodo presentan una viscosidad relativamente elevada, que varía de aproximadamente 15 a aproximadamente 60 mPa·s a temperatura ambiental. En general, los medios de contraste en que el agente potenciador del contraste es un dímero tienen una viscosidad mayor que los correspondientes medios de contraste en que el agente potenciador del contraste es el monómero correspondiente al dímero. Dichas viscosidades elevadas pueden plantear problemas a los administradores del medio de contraste, requiriendo agujas de calibre relativamente grande o una elevada presión de aplicación, problemas que son particularmente acusados en radiografía pediátrica y en técnicas radiográficas que requieren la rápida administración de un bolo, por ejemplo, en angiografía. X-ray contrast media with a high commercial concentration of iodine have a relatively high viscosity, ranging from about 15 to about 60 mPa · s at room temperature. In general, the contrast media in which the contrast enhancing agent is a dimer has a viscosity greater than the corresponding contrast media in which the contrast enhancing agent is the monomer corresponding to the dimer. Such high viscosities can pose problems for contrast media administrators, requiring relatively large needles or high application pressure, problems that are particularly pronounced in pediatric radiography and radiographic techniques that require rapid bolus administration, for example. , in angiography.
A los medios de contraste para rayos X que contienen un compuesto químico como el (los) ingrediente(s) farmacéutico(s) activo(s) que tiene(n) dos grupos fenilo triyodados unidos por un grupo enlazante se hace normalmente referencia como dímeros o agentes de contraste dímeros. A lo largo de los años se ha propuesto una gran diversidad de dímeros yodados. Publicaciones de patente relevantes comprenden EP 1186305, EP 686046, EP 108638, EP 0049745, EP 0023992, WO 2003080554, WO 2000026179, WO 1997000240, WO 9208691, US 3804892, US 4239747, US 3763226, US 3763227 y US 3678152. En este momento está a la venta un medio de contraste que tiene un dímero no iónico yodado como ingrediente farmacéutico activo, el producto Visipaque™ que contiene el compuesto iodixanol. También está a la venta el compuesto Hexabrix™, que contiene ácido ioxáglico, un compuesto dímero iónico. X-ray contrast media containing a chemical compound such as the active pharmaceutical ingredient (s) that has two triiodinated phenyl groups linked by a linking group is usually referred to as dimers. or dimer contrast agents. Over the years, a great diversity of iodinated dimers has been proposed. Relevant patent publications comprise EP 1186305, EP 686046, EP 108638, EP 0049745, EP 0023992, WO 2003080554, WO 2000026179, WO 1997000240, WO 9208691, US 3804892, US 4239747, US 3763226, US 3763227 and US 3678152. At this time a contrast medium having an iodinated non-ionic dimer as an active pharmaceutical ingredient, the Visipaque ™ product containing the compound iodixanol, is available for sale. Also available is the Hexabrix ™ compound, which contains ioxagic acid, an ionic dimer compound.
El Documento US 5349085 A se refiere a agentes de contraste no iónicos para rayos X del mismo tipo general que 3 US 5349085 A refers to non-ionic contrast agents for X-rays of the same general type as 3
Claims (1)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO20073595 | 2007-07-12 | ||
| NO20073594 | 2007-07-12 | ||
| NO20073595 | 2007-07-12 | ||
| NO20073594 | 2007-07-12 | ||
| PCT/NO2008/000255 WO2009008734A2 (en) | 2007-07-12 | 2008-07-04 | Contrast agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2486296T3 true ES2486296T3 (en) | 2014-08-18 |
Family
ID=39811676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES08793873.4T Active ES2486296T3 (en) | 2007-07-12 | 2008-07-04 | Contrast agents |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US8920780B2 (en) |
| EP (1) | EP2178568B1 (en) |
| JP (3) | JP5340281B2 (en) |
| KR (2) | KR101555457B1 (en) |
| CN (4) | CN101687051A (en) |
| AU (1) | AU2008273037B2 (en) |
| BR (1) | BRPI0814811A2 (en) |
| CA (1) | CA2692646C (en) |
| CO (1) | CO6351754A2 (en) |
| DK (1) | DK2178568T3 (en) |
| ES (1) | ES2486296T3 (en) |
| HR (1) | HRP20140649T1 (en) |
| IL (1) | IL202487A (en) |
| NZ (1) | NZ581765A (en) |
| PL (1) | PL2178568T3 (en) |
| PT (1) | PT2178568E (en) |
| RU (1) | RU2469021C2 (en) |
| WO (1) | WO2009008734A2 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8920780B2 (en) * | 2007-07-12 | 2014-12-30 | Ge Healthcare As | Contrast agents |
| EP2385845A1 (en) * | 2009-01-09 | 2011-11-16 | Ge Healthcare As | Contrast media compositions |
| EP2493511B1 (en) * | 2009-10-29 | 2013-10-16 | GE Healthcare AS | Diagnostic composition comprising plasma cations having a superior safety profile |
| RU2012138280A (en) * | 2010-03-23 | 2014-04-27 | ДжиИ Хелткер АС | OBTAINING A STABILIZED DIAGNOSTIC COMPOSITION FOR X-RAY STUDY |
| US20130116554A1 (en) * | 2010-07-12 | 2013-05-09 | Ge Healthcare As | X-ray imaging at low contrast agent concentrations and/or low dose radiation |
| EP2655318B1 (en) | 2010-12-21 | 2018-06-20 | GE Healthcare AS | Desalination of a composition comprising a contrast agent |
| WO2012136813A2 (en) | 2011-04-07 | 2012-10-11 | Universitetet I Oslo | Agents for medical radar diagnosis |
| EP2758319B1 (en) | 2011-09-21 | 2016-06-08 | GE Healthcare AS | Packaging of contrast media |
| GB2496971A (en) * | 2011-11-25 | 2013-05-29 | Ge Healthcare As | Preparation of X-ray contrast agents |
| NO333914B1 (en) * | 2011-12-21 | 2013-10-21 | Ge Healthcare As | Stabilization of diagnostic X-ray composition |
| WO2013104690A1 (en) * | 2012-01-11 | 2013-07-18 | Ge Healthcare As | X-ray imaging contrast media with low iodine concentration and x-ray imaging process |
| AU2013323982B2 (en) * | 2012-09-27 | 2017-11-23 | Ge Healthcare As | Preparation of Ioforminol, an X-ray contrast agent |
| CA2881852A1 (en) * | 2012-09-27 | 2014-04-03 | Ge Healthcare As | Preparation of an intermediate compound of ioforminol |
| PL2917174T3 (en) * | 2012-11-12 | 2019-01-31 | Ge Healthcare As | Preparation of intermediates of x-ray contrast agents |
| SG11201504201RA (en) | 2012-12-19 | 2015-07-30 | Ge Healthcare As | Purification of x-ray contrast agents |
| MX2015013658A (en) | 2013-03-27 | 2016-02-18 | Ge Healthcare As | Method and reagent for preparing a diagnostic composition. |
| EP3077367B1 (en) * | 2013-12-06 | 2018-07-11 | GE Healthcare AS | Alternative process for the purification of an intermediate in the synthesis of non-ionic x-ray contrast agents |
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| GB9903109D0 (en) * | 1999-02-11 | 1999-04-07 | Nycomed Imaging As | Process |
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| EP1492776B1 (en) | 2002-03-27 | 2008-10-29 | FUJIFILM Corporation | Iodinated triglyceride analogs |
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| US8920780B2 (en) | 2007-07-12 | 2014-12-30 | Ge Healthcare As | Contrast agents |
| JP6723006B2 (en) | 2015-12-10 | 2020-07-15 | 株式会社オカムラ | Chair |
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- 2008-07-04 CN CN201410177453.1A patent/CN103951585A/en active Pending
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